The Mechanisms of Action and Emerging Novel Views on SGLT-2 Inhibitors in the Treatment of Cancer

Ava Moreno^*
*Correspondence: Ava Moreno, Department of Cancer Clinical Research, University of Valencia, 46010 Valencia, Spain, Email:

Keywords

SGLT-2 inhibitors • Cancer treatment • Metabolic alterations • Tumor microenvironment

Introduction

Sodium-Glucose Co-Transporter-2 (SGLT-2) inhibitors have revolutionized the management of type 2 diabetes mellitus by offering a novel mechanism for lowering blood glucose levels. These inhibitors, which include drugs such as dapagliflozin, empagliflozin, and canagliflozin, act by inhibiting the SGLT-2 protein in the proximal renal tubules, thereby reducing glucose reabsorption and promoting glycosuria. Beyond their glucose-lowering effects, SGLT-2 inhibitors have shown cardiovascular and renal benefits, prompting further investigation into their pleiotropic effects. In recent years, there has been growing interest in the potential anti-cancer properties of SGLT-2 inhibitors. Cancer cells exhibit altered metabolic pathways to support rapid proliferation and survival, a phenomenon known as the Warburg effect, characterized by increased glucose uptake and glycolysis even in the presence of oxygen. Given the role of SGLT-2 inhibitors in modulating glucose metabolism, researchers have hypothesized that these drugs could influence cancer cell metabolism and growth. This review aims to explore the mechanisms by which SGLT-2 inhibitors may exert anti-cancer effects and to discuss emerging novel views on their potential role in oncology [1].

Literature Review

The anti-cancer potential of SGLT-2 inhibitors has been a topic of considerable research interest. Early studies focused on the direct effects of these inhibitors on cancer cell lines. In vitro experiments have demonstrated that SGLT-2 inhibitors can reduce glucose uptake in cancer cells, leading to decreased proliferation and increased apoptosis. For instance, research on prostate cancer cells has shown that dapagliflozin reduces cell viability by inhibiting glucose uptake and inducing oxidative stress. Similar effects have been observed in breast cancer and pancreatic cancer cell lines. Beyond direct effects on cancer cells, SGLT-2 inhibitors also modulate the tumor microenvironment. The tumor microenvironment, which includes stromal cells, immune cells, and extracellular matrix components, plays a critical role in cancer progression and response to therapy [2].

SGLT-2 inhibitors have been shown to impact various aspects of the tumor microenvironment. For example, they can reduce hypoxia by decreasing the metabolic demand of cancer cells, thereby improving the efficacy of radiation therapy. Additionally, SGLT-2 inhibitors can modulate immune cell infiltration and activity within tumors, enhancing anti-tumor immune responses. Preclinical studies using animal models have provided further evidence of the anti-cancer effects of SGLT-2 inhibitors. In murine models of breast cancer, treatment with empagliflozin resulted in significant tumor growth inhibition and improved survival. These findings were associated with reduced glucose uptake, decreased glycolytic activity, and increased apoptosis in tumor cells. Moreover, combination therapy with SGLT-2 inhibitors and other anti-cancer agents has shown synergistic effects in preclinical models, suggesting that these inhibitors could enhance the efficacy of existing treatments [3].

Discussion

The potential mechanisms underlying the anti-cancer effects of SGLT-2 inhibitors are multifaceted and involve both direct and indirect pathways. One of the primary mechanisms is the inhibition of glucose uptake in cancer cells. Cancer cells rely heavily on glucose for energy production and biomass synthesis. By blocking glucose reabsorption in the kidneys, SGLT-2 inhibitors reduce systemic glucose levels, which in turn limits the availability of glucose for cancer cells. This glucose deprivation can lead to energy stress, impaired proliferation, and increased cell death. In addition to glucose deprivation, SGLT-2 inhibitors can induce metabolic reprogramming in cancer cells. The inhibition of glucose uptake forces cancer cells to rely on alternative energy sources, such as fatty acids and amino acids [4].

This metabolic shift can create a state of metabolic vulnerability, making cancer cells more susceptible to apoptosis and other forms of cell death. Furthermore, the increased reliance on oxidative phosphorylation in the absence of sufficient glucose can lead to elevated levels of Reactive Oxygen Species (ROS), further promoting cancer cell death. Another important mechanism involves the modulation of the tumor microenvironment. SGLT-2 inhibitors can reduce tumor-associated hypoxia, a condition that promotes tumor progression and resistance to therapy. By decreasing the metabolic demand of cancer cells and reducing lactate production, these inhibitors can alleviate hypoxia and improve oxygenation within tumors. This improved oxygenation can enhance the efficacy of radiation therapy, which relies on the presence of oxygen to generate ROS and cause DNA damage in cancer cells [5].

SGLT-2 inhibitors also have immunomodulatory effects that can contribute to their anti-cancer properties. The tumor microenvironment is often characterized by immune suppression, with cancer cells evading immune surveillance. SGLT-2 inhibitors can enhance anti-tumor immune responses by modulating the activity and infiltration of immune cells. For example, these inhibitors can increase the infiltration of cytotoxic T cells and decrease the presence of regulatory T cells within tumors. Additionally, SGLT-2 inhibitors can reduce the production of immunosuppressive cytokines, thereby promoting a more immunogenic tumor microenvironment. Emerging evidence suggests that SGLT-2 inhibitors may also have direct effects on Cancer Stem Cells (CSCs), a subpopulation of cells within tumors that possess self-renewal and tumor-initiating capabilities. CSCs are often resistant to conventional therapies and contribute to tumor recurrence and metastasis. Studies have shown that SGLT-2 inhibitors can target CSCs by disrupting their metabolic processes and reducing their viability. This targeting of CSCs could potentially improve treatment outcomes and reduce the risk of relapse [6].

Conclusion

SGLT-2 inhibitors represent a promising new avenue for cancer treatment, with potential mechanisms of action that include glucose deprivation, metabolic reprogramming, modulation of the tumor microenvironment, and targeting of cancer stem cells. Preclinical studies have provided compelling evidence of the anti-cancer effects of these inhibitors, and emerging clinical data suggest potential benefits in cancer patients. However, further research is needed to fully elucidate the mechanisms underlying these effects and to optimize the use of SGLT-2 inhibitors in oncology. The future of SGLT-2 inhibitors in cancer treatment will likely involve combination strategies with other therapies to enhance their efficacy and overcome resistance. Additionally, personalized approaches that consider the metabolic characteristics of the tumor may help identify patients who are most likely to benefit from these drugs. As our understanding of cancer metabolism continues to evolve, SGLT-2 inhibitors may play an increasingly important role in the therapeutic arsenal against cancer.

Acknowledgement

None.

Conflict of Interest

None.

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